Abstract

Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficiency of phenylalanine hydroxylase (PAH). Demonstration
of mutations in the PAH gene establishes PAH deficiency as the cause of hyperphenylalaninaemia in the newborn and provides a basis for predicting
the metabolic phenotype and anticipating the dietary requirements of the patient. Mutations in the PAH gene are well archived in the PAH Locus Knowledgebase. Loss of PAH protein is a consequence of misfolding, aggregation and
accelerated degradation of the enzyme. BH4 rescues the activity of mutant PAH enzymes by functioning as a chaperone to stabilise enzyme structure or by overcoming defects
that alter the Km for BH4. Defects in BH4 metabolism can be divided into those associated with hyperphenylalaninaemia and those presenting without hyperphenylalaninaemia.
The diagnosis of BH4 deficiencies has to be considered for all conditions with hyperphenylalaninaemia. The measurement of pteridines in urine
discriminates BH4 synthesis deficiency from PKU children. Therapy is aimed at normalising Phe levels and brain neurotransmitters (Matalon et al., 2006). Treatment includes a special diet and/or BH4 supplements.

Key Concepts:

Deficiency of phenylalanine hydroxylase (PAH; E.C. 1.14.16.1.) is caused by mutations in the PAH gene.

PAH is inherited in an autosomal recessive pattern (MIM #261600).

PAH deficiency is a highly heterogeneous disorder that has been divided into four arbitrary phenotype categories: classic,
moderate and mild PKU, and mild hyperphenylalninaemia (MHP).

More than 450 mutated versions of PAH have been reported worldwide, each producing a protein with partial or total loss of
enzyme activity.

A clear correlation between genotype and phenylalanine tolerance has been documented and genotype/phenotype correlations are
established on the basis of patient data.

A continuum of phenylalanine hydroxylase‐deficiency phenotypes. Arbitrary phenotype categories may be defined on the basis
of phenylalanine tolerance, that is, the amount of dietary phenylalanine tolerated while keeping serum phenylalanine concentrations
within the desired therapeutic range. Pretreatment phenylalanine levels broadly correlate with disease severity, but cannot
be used reliably for anticipating dietary requirements in individual patients. MHP, mild hyperphenylalaninaemia.

Figure 2.

Concept of functional hemizygosity in phenylalanine hydroxylase (PAH) deficiency. Functionally hemizygous patients carry on one of their chromosomes a null PAH mutation, that is, a mutation that produces no PAH activity. Like the homozygous constellation, the functionally hemizygous constellation produces only homopolymeric enzyme.
Accordingly, the mutation on the nonnull allele determines the phenylalanine‐hydroxylating capacity and hence the phenotypic
outcome.